TY - JOUR
T1 - Tuning T cell signaling sensitivity alters the behavior of CD4 + T Cells during an Immune Response
AU - Viehmann Milam, Ashley A.
AU - Bartleson, Juliet M.
AU - Donermeyer, David L.
AU - Horvath, Stephen
AU - Durai, Vivek
AU - Raju, Saravanan
AU - Yu, Haiyang
AU - Redmann, Veronika
AU - Zinselmeyer, Bernd
AU - Michael White, J.
AU - Murphy, Kenneth M.
AU - Allen, Paul M.
N1 - Publisher Copyright:
Copyright 2018 by The American Association of Immunologists, Inc.
PY - 2018/5/15
Y1 - 2018/5/15
N2 - Intricate processes in the thymus and periphery help curb the development and activation of autoreactive T cells. The subtle signals that govern these processes are an area of great interest, but tuning TCR sensitivity for the purpose of affecting T cell behavior remains technically challenging. Previously, our laboratory described the derivation of two TCR-transgenic CD4 T cell mouse lines, LLO56 and LLO118, which recognize the same cognate Listeria epitope with the same affinity. Despite the similarity of the two TCRs, LLO56 cells respond poorly in a primary infection whereas LLO118 cells respond robustly. Phenotypic examination of both lines revealed a substantial difference in their surface of expression of CD5, which serves as a dependable readout of the self-reactivity of a cell. We hypothesized that the increased interaction with self by the CD5-high LLO56 was mediated through TCR signaling, and was involved in the characteristic weak primary response of LLO56 to infection. To explore this issue, we generated an inducible knock-in mouse expressing the self-sensitizing voltage-gated sodium channel Scn5a. Over-expression of Scn5a in peripheral T cells via the CD4-Cre promoter resulted in increased TCR-proximal signaling. Further, Scn5a-expressing LLO118 cells, after transfer into BL6 recipient mice, displayed an impaired response during infection relative to wild-type LLO118 cells. In this way, we were able to demonstrate that tuning of TCR sensitivity to self can be used to alter in vivo immune responses. Overall, these studies highlight the critical relationship between TCR–self-pMHC interaction and an immune response to infection.
AB - Intricate processes in the thymus and periphery help curb the development and activation of autoreactive T cells. The subtle signals that govern these processes are an area of great interest, but tuning TCR sensitivity for the purpose of affecting T cell behavior remains technically challenging. Previously, our laboratory described the derivation of two TCR-transgenic CD4 T cell mouse lines, LLO56 and LLO118, which recognize the same cognate Listeria epitope with the same affinity. Despite the similarity of the two TCRs, LLO56 cells respond poorly in a primary infection whereas LLO118 cells respond robustly. Phenotypic examination of both lines revealed a substantial difference in their surface of expression of CD5, which serves as a dependable readout of the self-reactivity of a cell. We hypothesized that the increased interaction with self by the CD5-high LLO56 was mediated through TCR signaling, and was involved in the characteristic weak primary response of LLO56 to infection. To explore this issue, we generated an inducible knock-in mouse expressing the self-sensitizing voltage-gated sodium channel Scn5a. Over-expression of Scn5a in peripheral T cells via the CD4-Cre promoter resulted in increased TCR-proximal signaling. Further, Scn5a-expressing LLO118 cells, after transfer into BL6 recipient mice, displayed an impaired response during infection relative to wild-type LLO118 cells. In this way, we were able to demonstrate that tuning of TCR sensitivity to self can be used to alter in vivo immune responses. Overall, these studies highlight the critical relationship between TCR–self-pMHC interaction and an immune response to infection.
UR - http://www.scopus.com/inward/record.url?scp=85047066759&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1701422
DO - 10.4049/jimmunol.1701422
M3 - Article
C2 - 29618523
AN - SCOPUS:85047066759
SN - 0022-1767
VL - 200
SP - 3429
EP - 3437
JO - Journal of Immunology
JF - Journal of Immunology
IS - 10
ER -